Method and preparations for relieving pain and producing analgesia

ABSTRACT

A method of treating a host for inducing relief of pain or anesthesia which comprises administering histamine, its salts, or an agent inducing histamine release, and a dispersing agent such as hyaluronidase, at the place of the painful area or at the place indicated for acupuncture for the painful site.

United States Patent 1 1 Revici Aug. 5, 1975 [75] Inventor: EmanuelRevici, New York, NY.

[73] Assignee: American Lipids Corporation, New

York. NY.

[22] Filed: Sept. 19, 1973 [21] App]. No.: 398,601

[52] US. Cl 424/94; 424/273 [51] Int. Cl. A61K 19/00 [58] Field ofSearch 424/94, 273

[56] References Cited OTHER PUBLICATIONS Merck Index, 7th Edition (I960)pages 520 & 521.

Societe, Chem. Abst. Vol. 75 (1971) page 52828u.

Lechat. Chem. Abst. Vol. 71 (1969) page 69229qv Keele, Chem. Abst. Vol.67 (1967) page 1507r.

Barnard. Chem. Abst. Vol. 60 (1964), page 5287a.

Primary E.\'aminer-Sam Rosen Attorney, Agent, or FirmPennie & Edmonds l5 7 1 ABSTRACT A method of treating a host for inducing relief of painor anesthesia which comprises administering histamine, its salts, or anagent inducing histamine release, and a dispersing agent such ashyaluronidase, at the place of the painful area or at the placeindicated for acupuncture for the painful site.

9 Claims, N0 Drawings METHOD AND PREPARATIONS FOR RELIEVING PAIN ANDPRODUCING ANALGESIA BACKGROUND OF THE INVENTION 1. Field of theInvention:

This invention relates to a method and preparations for relieving painand producing analgesia.

2. Description of the Prior Art:

A great deal of research has been performed on the effect of histamineand related compounds, both in vivo and in vitro. The literature on thissubject is so vast and conflicting that it is simply not practical toset forth any meaningful discussion on the subject. For example,Rosenthal et al. have reported in Am. J. Physiol. 155, 18690 1948) thatpainful sensations are produced by the injection of histamine and in theProc. Soc. Ecptl. Biol. Med. 74, 167-70 (1950) that histamine introducedinto the superficial layers of human skin causes an immediate well aslatent painful sensation. Jacob et al.. Am. inst. Pasteur 81, 12892(1951), have reported that histamine dil-ICI given to ratssubcutaneously or intraperitoneally for 6 to 30 days decreased theirsensitivity to thermal induced pain, but which returned after cessationof treatment.

Similarly a great deal of research has been performed with spreadingagents such as the hyaluronidase enzyme. Hyaluronidase has been usedalone and in combination with various drugs. The use of hyaluronidaseand histamine has also been studied. For example, it has been reportedby Seelich et al., Nature 168, 1125 (1951 that histamine does notneutralize heparin inhibitian of hyaluronidase and by Mathies et al., inZ. ges. exptel. Med. 133, 3237 (1960), that the inhibitary action ofphenylbutazone against hyaluronidase could be blocked by thesimultaneous administration of an antihistaminic agent. A vast amount ofadditional publications exist, both with respect to histamine andhyaluronidase, none of which, to applicants knowledge, disclose or teachthe invention disclosed and claimed herein.

SUMMARY OF THE INVENTION It has been found that administering histamine,its salts. compounds inducing histamine release, and dispersing agentsuch as hyaluronidase, or derivatives of histamine, having substantiallythe same pharmacological activity of histamine, directly to the painfularea or at the sites indicated for acupuncture for that painful area,will relieve the pain and produce analgesia at the painful area.

The term. histamine. is used herein in its generic sense, to includehistamine, its non-toxic salts, compounds which induce histamine releasein the body and histamine derivatives which produce a similarpharmacological activity within the body.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Histamine. its non-toxic salts,compounds inducing histamine release, and histamine derivatives having asimilar pharmacological activity in the body are well known and theirproperties and pharmacological action well documented in the literature.All such compounds are operable so long as they are capable ofdepositing directly or indirectly a sufficient amount of histamine incombination with hyaluronidase to induce analgesia or relief of pain.The main object is to impart by injection to the painful area or at theacupuncture sites histamine or a related compound having the samepharmacological action as histamine in combination with hyaluronidase.Whether this is accomplished by use of histamine itself or its non-toxicsalts, or in any other manner, is not material and is to be consideredwithin the present invention.

The dispersing or spreading factor can be a hyaluronidase of differentorigins, for example, from honey-bee venom, snake venom, etc.z-N-acetylglucosamidase has been found to be most efficient. Thesedispersing agents or factors and the methods by which they may beobtained are well known in the art.

The pain relieving or analgesic compositions of this invention can beprepared for injection by placing the histamine compound andhyaluronidase in a suitable medium, such as water, saline solution,isotonic solution, etc., with proper sterilization, as will be apparentto those skilled in the art.

The histamine compound and the hyaluronidase can be separately injectedinto the painful area or the acupuncture site for that painful area, butit is, of course, more convenient to combine the histamine compound andthe hyaluronidase in a convenient solution.

The concentration of the hyaluronidase enzyme, because of its variableactivity, depending upon its source and other well known factors, isgiven in units as set by the National Formulary. The unit concentrationis given on each package as units NF (TR) per volume of weight.

The amount of histamine and/0r hyaluronidase that can be injected willdepend upon the particular patient being treated, the extent of thepainful area, and the degree of pain. A sufficient amount of thehistamine compound and the hyaluronidase should, of course, be injectedto overcome the pain as will be apparent to any physician.

With respect to the histamine compound, the minimum amount has so farbeen determined to be about 0.01 mg., and with respect to thehyaluronidase about 10 units NF (TR), [hereinafter referred to as unitsor units per ml.]. Lower amounts could be used if conditions soindicate.

The maximum amount of the histamine compound that can be used willdependsomewhat upon the patient and his tolerance to flushes due to histaminereaction. Generally, amounts up to 0.5 mg. can be tolerated.

The maximum amount of hyaluronidase that can be used will again dependupon the particular patient to be treated as well as the amount ofhistamine being injected. Investigation to date indicated that one wouldnot require more than 50 units of hyalurondase.

Thus, the preparations of this invention can be prepared in such amanner so that the patient can receive between about 0.01 mg. and 0.05mg. of histamine and between about 10 and about 50 units ofhyaluronidase. Experiments to date have shown that an injection of 0.02mg. of histamine and 10 units of hyaluronidase is advantageous.

The solutions can he made up in varying concentrations and the totalvolume injected will, of course, depend upon the concentration of thesolution. For example, if a solution is made up to contain 0.02 mg. ofhistamine per ml. and 10 units of hyaluronidase per ml., an injection of1 ml. of this solution into the painful area or the acupuncture siteshould be sufficient.

The solutions can be injected into the painful area by anymeanssufficient to relieve the pain. such as, subcataneously, or deeper intothe tissues, periaticular, or even in the articulations, or in the sitesused for acupuncture. Depending upon the area of pain, one injection maysuffice or,- if the painful area is larger, the composition orpreparation may be injected into a plurality of places in the painfularea, such asin Example l,set forth below. Such a procedure is referredto herein as infiltration of the painful area. For example, in bursitis,at times, no burt can be located and in which case the entire painfularea, the shoulder for example. may be infiltrated, injecting the totalamount of desired histamine and hyaluronidase into the shoulder at aplurality of sites. In this case it may be, at times, desirable to havea more diluted solution, so that a larger area can be infiltrated and,at the same time, decrease the chance of-any histamine reaction by thepatient. Thus, the two main defects of the method, the missing-of thepainful spots and the flushes due to histaminic action, are controlledby this infiltration technique. using more diluted solutions ofhistamine.

As previously mentioned the method of this invention can also bepracticed by injecting the preparations at the acupuncture sites for theareas in which it is desired to relieve pain or produce analgesia. Thesesites are well known and are described for example, in ACU- PUNCTURETHERAPY, CURRENT CHINESE PRACTICE, by T. Tan, Y-C. Tan and Veith, TempleUniversity Press, Philadelphia, 1973.

One advantage of this acupuncture technique is the fact that the resultsare not the function of the capacity of the individual to respond to theneedle insertion with the liberation of histamine, and the use of thisinvention results in increased responses in the patient. Anotheradvantage is the fact that the injection of the preparations, accordingto this invention, will affect the entire area or acupuncture siterather than just a single point, and the chances of having the necessaryacupuncture site influenced is thus highly increased. The preparationsof thisinvention can thus be used for the treatment of differentconditions for which acupuncture is presently used, such as for theinduction of anesthesia for surgical interventions.

It has also been noted that together with the suppression of the pain,the evolution of lesions also appears to be influenced.

In all cases where a patient is treated, as a precautionary measure, ananthistamine injection or adrenaline for injection was kept available incase of hypersensitivity to histamine. It is interesting to note,however, that in over 100 cases treated so far there was no need to useeither the histaminic preparation or adrenaline, even in a case (Examplel) of the patient who had a history of servere histamininc reactions.

The following examples illustrate the practise of the invention:

EXAMPLE 1 A 60 year old male with severe pain and totally immobilized bya frozen shoulder" due to bursitis. The condition had gottenprogressively worse over the last two months and did not respond tovarious treatments. From a solution containing 0.2 mg. of histaminephosphate and l0 units of hyaluronidase per ml., 2' ml. divided in 4injections were injected in the painful spots. The pain disappeared inless than 6 minutes, with recovery of movement. Seen after 2 weeks, the;good effects were persistent.

EXAMPLE ,2

A 58 year old female with severe arthritis pain in the coccidial regionfor several months. The pain could not be controlled by varioustreatments. From a solution containing 0.05 mg. of histamine phosphateand 10 units of. hyaluronidase per ml. 1 ml. was injected in thepainfularea. The pain disappeared in 4 minutes and remained as such atan examination one month later.

EXAMPLE 3 A 50 year old male with pain due to a sciatica of the left.leg, not responding to treatments for the last month. A total of 3 ml.of a preparation containing 0.05 mg. of histamine and 10 units ofhyaluronidase per ml. was injecteddeep subcutaneously in 5 differentpainful spots. The pain disappeared and remained as such after 2 months.

EXAMPLE 4 EXAMPLE 5 A year old female .with pains in the left knee, andunable to localize the pain otherwise than the entire anterior area ofthe knee. A subcutaneous infiltration of this region with 10 ml. of asolution containing 0.01 mg. per ml. of histamine phosphate and 10 unitsof hyaluronidase per ml. was followed by the disappearance and withoutrecurrence of the pain after 12 days..

EXAMPLE 6 A 62 year old female with severe pain in the left sacroiliacarticulation, persisting for months. A subcataneous injection of 0.5 ml.of a solution containing 0.2 mg. per ml. of histamine and 10 units ofhyaluronidase per ml. at the painful area did not completely suppressthe pain after l5 minutes. A same amount of the solution injected deepinto the articulation fully controlled the pain, with the effect stillpersisting after 3 weeks.

EXAMPLE 7 A 50 year old male with acancer of the spine, at the 10-12 Dand 1 D forwhich a decompressioin intervention was performed. Thepatient had very severe pain, on both sides of the lesion, onlyinsufficiently controlled by opiates. From a solution containing 0.2 mg.of histamine phosphate per ml. and 10 units of hyaluronidase per ml.,several injections totalling 1.5. ml. weremade only at the right side ofthe spine. The pain disappeared after 6 minutes and still did notreappear after one week, while the pain persisted unchanged in the leftside of the spine. The same injection in left side hadfthe same goodeffect.

EXAMPLE 8 A 40 year old male with severe backache. The pain- I ful areawas injected with 2 ml. of a 0.1 percent by weight solution of compound48/80 and l units of hyaluronidase per ml. in a saline (sterilized byfiltration). The pain was controlled in about 15 minutes and the effectstill persisted after one week.

EXAMPLE 9 A 63 year old male with pains in the elbow after playingtennis. The pain persisted for weeks, in spite of treatment. A localinfiltration of 7.5 ml. of a solution containing 0.02 mg. per ml. ofhistamine and 20 units of hyaluronidase per ml. was injected locally.The pain disappeared in minutes. The patient did not have any flushingsensation.

EXAMPLE 10 A 30 year old male with a very painful shoulder ofosteoarthritic nature. An infiltration of the entire painful area. withml. ofa solution containing 0.1 mg. of histamine per ml. and 10 units ofhyaluronidase was made. The pain was controlled in less than 10 minutes.The patient remained without pain 6 weeks after the infiltration. Thepatient, who had a severe histaminic reaction because of a prior use ofhistamine for a gastric test. with headache. itching and vision troublesdid not have any adverse reaction after treatment.

As can be seen from the above examples, abdominal pain from ovaryinflammation and gallbladder colics wee controlled by deep subcutaneousinjections in the painful areas. Even cancer pains responded well to theinjections. Good results were obtained for different neuralgias. such assciatica. tic douloureux. post Zonz Zoster neuralgia. with injectionsmade locus dolendi" (painful spots). The effects were good also infractures and especially in residual pains after trauma. ln gen eral.with only very few exemptions. the results in more than 100 casestreated are exceptionally good. with not only the pain immediatelycontrolled and with functional recovery, but with the results lastingfor a long period of time, weeks or even months after the injections.The pain entirely disappears in less than about 15 minutes in mostcases. In some cases the pain was felt after one or two days, but inthese cases the pain was felt in areas other than those injected. Nolocal numbness was noted.

I claim:

1. A method of relieving pain or producing analgesia in a host whichcomprises injecting a solution of histamine. or its non-toxic salts. anda hyaluronidase at the painful area or at the acupuncture sites for thearea in which it is desired to relieve pain or produce analgesia in ahost in a sufficient amount to relieve'the pain or produce analgesia.

2. The method of claim 1, wherein the preparation is infiltrated at thepainful area.

3. The method of claim 1 in which the histamine and hyaluronidase areinjected in admixture.

4. A method of claim 1, wherein the hyaluronidase isz-N-Acetylglucosamidase hyaluronidase.

5. The method of claim 1, wherein the solution contains from about .01to about 0.5 mgs. of histamine per ml.

6. The method of claim 5, wherein the solution contains from about 10 toabout 50 NF (TR) units of hyaluronidase.

7. Preparations for use in relieving pain or for producing analgesiawhich comprise a sterile solution of histamine or its non-toxic salts,and a hyaluronidase containing between about .01 mg. to about 0.5 mg.histamine per ml. and between about 10 to about 50 NF (TR) units of thehyaluronidase.

8. The preparation of claim 7 wherein the ingredients are combined witha non-toxic liquid carrier.

9. A preparation of claim 8, wherein the carrier is water, salinesolution or an isotonic solution.

1. A METHOD OF RELIEVING PAIN OR PRODUCING ANALGESIA IN A HOST WHICHCOMPRISES INJECTING A SOLUTION OF HISTAMINE, OR ITS NON-TOXIC SALTS, ANDA HYALURONIDASE AT THE PAINFUL AREA OR AT THE ACUPUNCTURE SITES FOR THEAREA IN WHICH IT IS DESIRED TO RELIEVE PAIN OR PRODUCE ANALGESIA IN AHOST IN A SUFFICIENT AMOUNT TO RELIEVE THE PAIN OR PRODUCE ANALGESIA. 2.The method of claim 1, wherein the preparation is infiltrated at thepainful area.
 3. The method of claim 1 in which the histamine andhyaluronidase are injected in admixture.
 4. A method of claim 1, whereinthe hyaluronidase is z-N-Acetylglucosamidase hyaluronidase.
 5. Themethod of claim 1, wherein the solution contains from about .01 to about0.5 mgs. of histamine per ml.
 6. The method of claim 5, wherein thesolution contains from about 10 to about 50 NF (TR) units ofhyaluronidase.
 7. Preparations for use in relieving pain or forproducing analgesia which comprise a sterile solution of histamine orits non-toxic salts, and a hyaluronidase containing between about .01mg. to about 0.5 mg. histamine per ml. and between about 10 to about 50NF (TR) units of the hyaluronidase.
 8. The preparation of claim 7wherein the ingredients are combined with a non-toxic liquid carrier. 9.A preparation of claim 8, wherein the carrier is water, saline solutionor an isotonic solution.